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• This is the most common endocrine disorder diagnosed in females aged 18-44 years.
• It affects 2-20% depending on how it is defined.
• It is a disorder of the adrenal-ovarian endocrine axis.
• Affected females may have elevated adrenal and or ovarian androgens.
• It may present with a variety of symptoms that can remit or relapse over time.
• These include; irregular or no menses, menorrhagia, excess facial and/or body hair,
pelvic pain, subfertility/infertility, patches of thick darker velvety skin, truncal
obesity, difficulty losing weight (due to insulin resistance).
• It is one of the leading causes of infertility.
• Associated conditions include; Type 2 Diabetes , obstructive sleep apnoea, mood
disorders, and endometrial cancer.
• Other metabolic sequelae include; hypertension, dyslipidaemia, visceral obesity,
insulin resistance, hyperinsulinaemia and CHD.
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History of PCOS:
• First published description 1721 in Italy.
• Cyst-related ovarian changes described 1844.
• Other names for PCOS; polycystic ovary disease, functional
ovarian hyperandrogenism, ovarian hyperthecosis and Stein–
Leventhal syndrome.
• The last option only used for subset with amenorrhea, infertility,
hirsutism, enlarged PCO.
• Most common name for the disorder PCOS is based on the
finding at US of PCO. These ovaries have an abnormally large
number of developing eggs arrested in development.
• At US these cysts are usually peripheral and circumferentially
arranged within the ovary and appear as a ‘string of pearls’.
• Not all women with PCO will have PCOS and not all women with
PCOS have PCO.
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History of PCOS:
History of PCOS 1970-2018:
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Understanding PCOS
Neuro-endocrinology:
Hypothalamic Pituitary Ovarian Axis (HPOA)
Regulation Adrenal Gland:
Adrenal androgenesis
HPOA control of ovarian function:
Normal HPOA neuro-endocrine-regulation
Menstrual cycle and ovarian function:
Anatomy of the normal ovary:
Normal ovary versus PCO
Overview of PCOS:
PCOS: Epidemiology
Prevalence of PCOS:
• These may be asymptomatic carriers or have symptoms such as early baldness and/or
excessive hair) and daughters, who show signs of PCOS.
• The phenotype manifests itself at least partially via raised androgen levels secreted by
ovarian follicle theca cells from women with the allele.
• The exact gene has not yet been identified. In In rare instances, single-gene mutations can
give rise to the phenotype of PCOS.
• Current understanding of the pathogenesis suggests it is a complex multigenic disorder.
PCOS Genetics
Aetiology of PCOS: Obesity
• Severity of PCOS symptoms appears largely determined by
factors such as obesity. PCOS has some aspects of a
metabolic disorder since symptoms are partly reversible.
Considered a gynecological problem, PCOS consists of 28
clinical symptoms.
• PCOS suggests ovaries central to disease pathology but
cysts are symptoms not cause. Some symptoms persist
even with removal of the ovaries. PCOS can appear minus
ovarian cysts.
• Gynecologists see it as a gynecological wth ovaries being
the primary organ affected. However, research identifies a
multisystem disorder, the main issue is
hypothalamichormonal regulation, with the involvement
of many organs.
• PCOD is used when there is US evidence and the term
PCOS where there is a wider spectrum of symptoms. Cysts
are only seen in 15% PCOS cases.
• PCOS may be related or worsened by exposure during the
prenatal period, epigenetic or environmental factors
(especially industrial endocrine disruptors e.g. bisphenol
A) and certain drugs) as well as increasing rates of obesity.
• IUGR increase risk of adult metabolic syndrome and PCOS
Fetal Growth Restriction and PCOS:
PCOS: Pathogenesis
Pathogenesis of PCOS:
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PCOS- Definitions and
diagnostic criteria
Two definitions are commonly used:
• NIH: In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person
has PCOS if they have all of the following: Oligoovulation, signs androgen excess (clinical or
biochemical), exclude disorders that result in menstrual irregularity and hyperandrogenism.
• Androgen Excess PCOS Society: In 2006, the Androgen Excess PCOS Society suggested a
tightening of the diagnostic criteria to all of the following: excess androgen activity,
oligoovulation/anovulation and/or PCO, exclusion of other entities causing excess androgen.
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Features of PCOS:
• Menstrual: PCOS mostly produces oligo-menorrhoea (fewer than nine menstrual periods in a
year) or amenorrhoea (no menstrual periods for 3 or more consecutive months), but other
types of menstrual disorders may also occur.
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Patient assessment and diagnosis
Patient assessment
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Hirsutism: Ferriman Galway Score:
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Differential diagnosis
• If signs of virilisation (e.g. deep voice, reduced breast size, increased muscle bulk,
clitoral hypertrophy), rapidly progressing hirsutism (<1 year between hirsutism being
noticed and seeking medical advice), then exclude other diagnoses.
• High total testosterone levels (> 5 nmol/l or >2 upper limit normal range) exclude
androgen-secreting tumours and late-onset/non-classical Congenital Adrenal
Hyperplasia (CAH).
• 17-OH Progesterone should be measured in follicular phase and will be raised in CAH.
• It is possible to have CAH without testosterone >5 nmol/l, particularly if the woman is
heterozygous for this condition. Hence measurement of 17-hydroxyprogesterone with
high index of suspicion (e.g. Ashkenazi Jews, or family history of CAH).
• Since management of CAH is different than that of PCOS if 17-OH Progesterone is
borderline, it will have to be confirmed by an ACTH stimulation test to diagnose CAH.
• If clinical suspicion of Cushing’s syndrome or acromegaly, this should be investigated
as per local practice.
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Other diagnostic considerations
• It should be noted that the diagnosis of PCOS can only be made when other
aetiologies for irregular cycles, such as thyroid dysfunction, acromegaly or
hyperprolactinaemia, have been excluded if there is clinical suspicion.
• Women with non-Caucasian ethnicity might need different criteria to diagnose PCOS.
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PCOS treatment:
Treatment
Lifestyle measures;
Weight loss
Exercise
Low CHO diet
Homeopathy dietary supplements
Pharmacological therapies;
• Combined Oral Contraceptive (COC)
• Anti-Androgen (AA)
• Metformin
• Spironolactone
• Flutamide
• Inositol
• Ovarian drilling
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Treatment PCOS:
• Therapeutic approaches for adult patients not seeking fertility include combined oral
contraceptives (COC), antiandrogens (AA) and/or insulin sensitizers, although these practices
are supported by limited high-quality evidence.
• Metanalysis published Human Reproduction 2017; COC versus AA versus Metformin alone of
in combination for the treatment of PCOS. Outcome measures included hirsutism scores, IR,
BMI, menses pattern, BP, lipid profile, GTT.
• COC and AA are more effective than metformin for hyperandrogenic symptoms and
endometrial protection. Their combination with metformin adds a positive effect on BMI and
glucose tolerance.
• Examples COC; Yasmin Microgynon etc
• Examples COC +AA; Dianette (Cyproterone Acetate)
• Examples AA; Cyproterone Acetate
• Examples AA; Spironolactone or Flutamide
PCOS and Metformin:
• Metformin was logically introduced to establish the extent to which
hyperinsulinaemia influences the pathogenesis of PCOS.
• Early studies were very encouraging but RCTs and several meta-analyses have
changed the picture.
• In PCOS failure of the target cells to respond to normal or ordinary levels of insulin
is regarded as insulin resistance (IR).
• IR leads to a compensatory increased production of insulin by the pancreatic beta
cells to control the hyperglycaemia which ultimately fails leading to T2DM.
• In PCOS, hyperinsulinaemia has been thought to increase hyperandrogenaemia via
a central role or by decreasing the circulating levels of SHBG.
• IR is not considered a diagnostic criterion in PCOS. However, it is recognized by
many as a common feature in PCOS independent of obesity
PCOS and Metformin:
• Metformin improves sensitivity of peripheral tissues to insulin reducing serum levels.
• Metformin inhibits hepatic gluconeogenesis and it also increases the glucose uptake by
peripheral tissues and reduces fatty acid oxidation.
• Metformin has a positive effect on the endothelium and adipose tissue independent of its
action on insulin and glucose levels.
• Main side effects are GI; nausea, diarrhoea, flatulence, bloating, anorexia, metallic taste and
abdominal pain. These symptoms occur with variable degrees in patients and in most cases
resolve spontaneously.
• Start dose of 500 mg daily during the main meal of the day for 1–2 weeks can lessen side
effects and allow tolerance to develop. A weekly or biweekly increase by 500 mg a day can
then be pursued up to maximum 2500–2550 mg/day.
• Slow release metformin can be associated with fewer side effects. Metformin can also lead to
vitamin B12 malabsorption in the distal ileum in approximately 10–30% of patients which is an
effect dependent on age, dose and duration of treatment.
Metformin in PCOS:
• Metformin works by reducing the circulating insulin levels.
• Conflicting evidence as to whether it can directly affect ovarian steroidogenesis.
• May restore ovulation, reduce weight, reducing circulating androgen levels, reducing the risk
of miscarriage and reducing the risk of gestational diabetes mellitus (GDM).
• Other studies have reported that the addition of metformin to the ovarian stimulation
regime in in vitro fertilization (IVF) improves the pregnancy outcome.
• The lack of an emphatic or overwhelming efficacy for Metformin in females with PCOS is
largely due to the patients' variability in phenotypes and their metabolic parameters. Some
studies have tried to identify the patients that are most likely to benefit from metformin, yet
again the results have not been forthcoming.
• Metformin does not replace the need for lifestyle modification among obese and overweight
PCOS women. The evidence categorically does not encourage its use to help weight loss
either although it may be useful in redistributing adiposity according to some evidence.
• The long-term use of Metformin to prevent remote complications of PCOS is uncertain and a
significant amount of work is needed before a decision can be made on this front.
Stipulations from studies carried out on the general population is not the same and can be
misleading given the diversity of PCOS patients with regard to their metabolic comorbidities.
•
Laparoscopic ovarian drilling:
• Laparoscopic drilling for PCOS was first used 1984 involving
multiple micro-perforations of the ovarian surface via diathermy or
LASER destroying ovarian stroma and peripheral follicles of PCOS.
• Punctures ovarian cortex 4–10 mm deep/3 mm wide and number
of punctures related to subsequent ability to conceive. 5-10
punctures more likely to produce conception.
• Use monopolar needle/hook and electrocoagulation at 40 W,
(range from 30-400 W). Laparoscopic approach < morbidity then
ovarian wedge resection.
• Aims to reduce the amount of androgen producing tissue, may
reduce circulating E2 levels, LH level/pulsations, and inhibin B.
• The most plausible theory is that reduction of these leads to an
increase in the secretion of FSH and SHBG leading to effective
follicular maturation and ovulation.
• Low serum E2 associated with <aromatase activity. IGF-1 produced
with injury aids effects of FSH through greater blood flow GnRH
delivery. AMH levels fall after drilling
• Goal of drilling treatment is induction of mono-ovulatory cycles.
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Laparoscopic ovarian drilling:
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Summary and audit topics:
Summary of the metabolic consequences of
PCOS and screening recommendations:
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Summary of cancer and PCOS: What are the risks and
how should these women be screened?
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Clinical standards and auditable topics:
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